In recent years, there have been exciting new advances for the treatment of ocular diseases such as age-related macular degeneration and diabetic retinopathy, using biotherapies. Because the eye is a small, confined organ, isolated by barriers, it has been identified as an organ of choice for local gene therapy.
For example, hereditary retinal dystrophies are due to mutations in gene encoding proteins in photoreceptors (cones and rods) or in retinal pigment epithelial cells (RPE). Whilst gene replacement in photoreceptor cells is still under pre-clinical evaluation, the most striking advances in this field have been made for RPE65 gene replacement in RPE cells, for the treatment of Leber congenital amaurosis (LCA). Not only was it shown that viral gene transfer in the RPE was feasible and efficient in animal models, but recently, patients have received the sub retinal injection of rAAV4 with promising functional results, providing hope for patients suffering from blinding diseases.
Viral vectors allow efficient transfection of RPE cells and have served to validate proof of concepts, but the long-term persistence of viral particles into the retina and the brain continues to raise safety concerns, particularly when treatment is being applied in young children.
When injected into the vitreous, viral vectors do not reach the RPE cells and only their sub-retinal injection have been shown effective for targeting RPE cells or photoreceptors. Moreover, using the sub retinal injection, RPE cells are only transfected in, and in the vicinity of the detached retina area, which implies detaching the macula when central vision recovery is targeted. Such a macular detachment may be associated with vision threatening. Indeed, it is well known that poor vision recovery after retinal detachment is correlated with macular detachment. Recent work using spectral domain OCT has provided evidence that following successful surgical treatment of retinal detachment, 62% of the eyes presented anatomical foveal abnormalities and that particularly, external limiting membrane disruption, observed only when the macula was detached before surgery, was associated with the worst vision prognosis. Even if controversies still exist regarding the factors that may predict vision recovery after macular detachment, the health of the macula at the time of reattachment is probably the most critical variable. In diseased eyes, knowing the uncertainty of central vision recovery after macular detachment, it is difficult to ensure that submacular injection is not risky.
Many non-viral gene transfer vectors or methods have been developed and adapted for ocular gene therapy (Andrieu-Soler C Mol Vis 2006 12:1334; Bejjani R A Sury Ophthalmol 2007 52:196; Bloquel C Adv Drug Deliv Rev 2006 58:1224). Among those, electroporation, also called “electrotansfer” where the current drives plasmid DNA into cells, is among the most efficient ((Mir L M Adv Genet 2005 54:83; Mir L M Methods Mol Biol 2008 423:3; Isaka Y Expert Opin Drug Deliv 2007 4:561) and has been developed up to clinical evaluation (Daud A I J Clin Oncol 2008 26:5896). Previous reports have shown that after sub retinal administration of the plasmids, electroporation allowed the efficient tranfection of new-born murine RPE (Matsuda T Proc Natl Acad Sci USA 2004 101:16) and delayed retinal degeneration in animal models (Chen B Science 2009 323:256). Efficient and prolonged RPE transfection was also achieved in the adult rat using a combination of sub retinal plasmids injection containing specific RPE promoter and electroporation (Kachi S Gene Ther 2005 12:843; Johnson C J Mol Vis 2008 14:2211).
The suprachoroidal space is a potential space in the eye that is located between the choroid, which is the inner vascular tunic, and the sclera, the outer layer of the eye. The suprachoroidal space extends from the anterior portion of the eye posterior to the ciliary body to the posterior portion of the eye up to the optic nerve. The suprachoroidal space of the eye has been thus studied as a possible route for drug delivery. See, e.g., Olsen, et al., American J. Opthamology 142(5): 777-87 (November 2006); PCT Patent Application Publication No. WO 2007/100745 to Iscience Interventional Corporation. The suprachoroidal space may indeed provide a potential route of access from the anterior region of the eye to treat the posterior region. However said route has not been envisaged for non-viral gene therapy.